Abstract A family of uncoupling proteins (UCPs), free fatty acid anion transporters, plays a crucial role in energy homeostatic thermoregulation. Tumor necrosis factor-α (TNF-α), a member of the cytokine family, is well known as an endogenous pyrogen. To evaluate the interaction of TNF-α with UCPs in thermogenesis, effects of TNF-α on rat UCP gene expression were examined in intrascapular brown adipose tissue (BAT), epididymal white adipose tissue (WAT) and soleus muscle (Muscle). Administration of TNF-α elevated rectal temperature by 0.7°C as well as serum leptin which peaked at 6 h, compared with saline controls. BAT UCP1 mRNA expression was increased by 1.2-fold at 6 h after the TNF-α treatment and decreased by 0.8-fold at 16 h after the treatment. In contrast to UCP1 expression in BAT, UCP2 mRNA expressions in BAT, WAT, and Muscle was increased to reach maximum levels of 1.3-, 1.6- and 1.8-fold, respectively, at 16 h after the treatment. UCP3 mRNA in Muscle, but not in BAT or WAT, was exclusively up-regulated by 1.7-fold at 16 h after the treatment. These results indicate that TNF-α up-regulates UCP gene expression differentially and tissue dependently, and add novel insights into thermogenesis under conditions of malignancy and inflammation.